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The etomidate analog ET-26 HCl retains superior myocardial performance: Comparisons with etomidate in vivo and in vitro.

ABSTRACT: (R)-2-methoxyethyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate hydrochloride (ET-26 HCl) is a novel etomidate analogue. The purpose of this study was to characterize whether ET-26 HCl could retain the superior myocardial performance of etomidate in vivo and in vitro.In vivo, the influence of ET-26 HCl and etomidate on the cardiac function of dogs was confirmed using echocardiography and electrocardiogram. In vitro, a Langendorff preparation was used to examine direct myocardial performance in isolated rat hearts, and a whole-cell patch-clamp technique was used to study effects on the human ether-a-go-go-related gene (hERG) channel.In vivo, after a single bolus administration of ET-26 HCl or etomidate, no significant difference in echocardiography and electrocardiogram parameters was observed. No arrhythmia occurred and no QT interval prolongation happened during the study period. In the in vitro Langendorff preparation, none of the cardiac parameters were abnormal, and the hERG recordings showed that ET-26 HCl and etomidate inhibited the tail current of the hERG in a concentration-dependent manner with an IC50 of 742.51 ?M and 263.60 ?M, respectively.In conclusion, through an in vivo experiment and a whole organ preparation, the current study found that ET-26 HCl can maintain a myocardial performance that is similar to that of etomidate. In addition, the electrophysiology study indicated that ET-26 HCl and etomidate inhibited the hERG at a supra-therapeutic concentration.

SUBMITTER: Liu X

PROVIDER: S-EPMC5764323 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The etomidate analog ET-26 HCl retains superior myocardial performance: Comparisons with etomidate in vivo and in vitro.

Liu Xingxing X Song Haibo H Yang Jun J Zhou Cheng C Kang Yi Y Yang Linghui L Liu Jin J Zhang Wensheng W

PloS one 20180111 1

<h4>Objective</h4>(R)-2-methoxyethyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate hydrochloride (ET-26 HCl) is a novel etomidate analogue. The purpose of this study was to characterize whether ET-26 HCl could retain the superior myocardial performance of etomidate in vivo and in vitro.<h4>Methods</h4>In vivo, the influence of ET-26 HCl and etomidate on the cardiac function of dogs was confirmed using echocardiography and electrocardiogram. In vitro, a Langendorff preparation was used to examine d ...[more]

PMID: 29324898

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Project description:BackgroundBecause etomidate induces prolonged adrenal suppression, even following a single bolus, its use as an infused anesthetic is limited. Our previous study indicated that a single administration of the novel etomidate analog methoxyethyletomidate hydrochloride (ET-26-HCl) shows little suppression of adrenocortical function. The aims of the present study were to (1) determine the minimum infusion rate of ET-26-HCl and compare it with those for etomidate and cyclopropyl-methoxycarbonylmetomidate (CPMM), a rapidly metabolized etomidate analog that is currently in clinical trials and (2) to evaluate adrenocortical function after a continuous infusion of ET-26-HCl as part of a broader study investigating whether this etomidate analog is suitable for long infusion in the maintenance of anesthesia.MethodThe up-and-down method was used to determine the minimum infusion rates for ET-26-HCl, etomidate and CPMM. Sprague-Dawley rats (n = 32) were then randomly divided into four groups: etomidate, ET-26-HCl, CPMM, and vehicle control. Rats in each group were infused for 60 min with one of the drugs at its predetermined minimum infusion rate. Blood samples were drawn initially and then every 30 min after drug infusion to determine the adrenocorticotropic hormone-stimulated concentration of serum corticosterone as a measure of adrenocortical function.ResultsThe minimum infusion rates for etomidate, ET-26-HCl and CPMM were 0.29, 0.62, and 0.95 mg/kg/min, respectively. Compared with controls, etomidate decreased serum corticosterone, as expected, whereas serum corticosterone concentrations following infusion with the etomidate analogs ET-26-HCl or CPMM were not significantly different from those in the control group.ConclusionThe corticosterone concentrations tended to be reduced for the first hour following ET-26-HCl infusion (as compared to vehicle infusion); however, this reduction did not reach statistical significance. Thus, further studies are warranted examining the practicability of using ET-26-HCl as an infused anesthetic.

Project description:ObjectiveET-26 HCl is a promising sedative-hypnotic anesthetic with virtually no effect on adrenocortical steroid synthesis. However, whether or not ET-26 HCl also has a sufficiently wide safety margin and hemodynamic stability similar to that of etomidate and related compounds remains unknown. In this study, the effects of ET-26 HCl, etomidate and propofol on therapeutic index, heart rate (HR), mean arterial pressure (MAP), maximal rate for left ventricular pressure rise (Dmax/t), and maximal rate for left ventricular pressure decline (Dmin/t) were investigated in healthy rats and a rat model of uncontrolled hemorrhagic shock (UHS).Methods50% effective dose (ED50) and 50% lethal dose (LD50) were determined after single bolus doses of propofol, etomidate, or ET-26 HCl using the Bliss method and the up and down method, respectively. All rats were divided into either the normal group and received either etomidate, ET-26 HCl or propofol, (n = 6 per group) or the UHS group and received either etomidate, ET-26 HCl or propofol, (n = 6 per group). In the normal group, after preparation for hemodynamic and heart-function monitoring, rats were administered a dose of one of the test agents twofold-higher than the established ED50, followed by hemodynamic and heart-function monitoring. Rats in the UHS group underwent experimentally induced UHS with a target arterial pressure of 40 mmHg for 1 hour, followed by administration of an ED50 dose of one of the experimental agents. Blood-gas analysis was conducted on samples obtained during equilibration with the experimental setup and at the end of the experiment.ResultsIn the normal group, no significant differences in HR, MAP, Dmax/t and Dmin/t (all P > 0.05) were observed at any time point between the etomidate and ET-26 HCl groups, whereas HR, MAP and Dmax/t decreased briefly and Dmin/t increased following propofol administration. In the UHS group, no significant differences in HR, MAP, Dmax/t and Dmin/t were observed before and after administration of etomidate or ET-26 HCl at ED50 doses (all P > 0.05). Administration of propofol resulted in brief, statistically significant reductions in HR and Dmax/t, with a brief increase in Dmin/t (P ˂ 0.05), while no significant differences in MAP were observed among the three groups. The blood-lactate concentrations of rats in the ET-26 HCl group were significantly lower than those in etomidate and propofol groups (P ˂ 0.05).ConclusionsET-26 HCl provides a similar level of hemodynamic stability to that obtained with etomidate in both healthy rats, and rat models of UHS. ET-26 HCl has the potential to be a novel induction anesthetic for use in critically ill patients.

Project description:Background5-Hydroxytryptamine type 3 (5-HT(3)) receptors are excitatory ion channels belonging to the cys-loop family of ligand-gated ion channels. They are involved in nausea and vomiting and their antagonists are used clinically as antiemetic drugs. We previously reported the development of a novel pyrrole analog of etomidate, (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), which retains etomidate's desirable anesthetic and hemodynamic properties, but lacks its potent inhibitory effect on adrenocorticotropic hormone-stimulated steroid synthesis. Also in contrast to etomidate, carboetomidate potently inhibits nicotinic acetylcholine receptors. Because nicotinic acetylcholine and 5-HT(3) receptors are highly homologous, we hypothesized that carboetomidate might also potently inhibit 5-HT(3) receptors with potentially important implications for the drug's emetogenic activity. In the current studies, we investigated and compared modulation of 5-HT(3A) receptors by carboetomidate and etomidate.Methods5-HT(3) receptors were heterologously expressed in human embryonic kidney cells. Drugs were applied with a multichannel superfusion pipette coupled to piezoelectric elements, and currents were recorded from cells in either the whole-cell or excised outside-out patch configuration of patch-clamp recordings.ResultsCarboetomidate and etomidate inhibited integrated 5-HT(3A) receptor-mediated currents with respective half-inhibitory concentrations of 1.9 μM (95% confidence interval [CI] = 1.4-2.7 μM) and 25 μM (95% CI = 17-37 μM). These values may be compared with respective hypnotic concentrations of 5.4 and 2.3 µM. This inhibition reflected hypnotic effects on peak current amplitudes and desensitization rates. Half-inhibitory concentrations for reducing peak current amplitudes were 34 μM (95% CI = 24-48 µM) for carboetomidate and 171 μM (95% CI = 128-228 µM) for etomidate. Half-inhibitory concentrations for reducing the desensitization time constant were 3.5 μM (95% CI = 2.4-5.1 µM) for carboetomidate and 36 μM (95% CI = 21-59 µM) for etomidate.ConclusionsIn contrast to etomidate, carboetomidate inhibits 5-HT(3A) receptor-mediated currents at hypnotic concentrations. This inhibition is primarily the result of enhancing the rate of desensitization. Because carboetomidate potently inhibits 5-HT(3A) receptors, it may be less emetogenic than etomidate.

Project description:BackgroundCarboetomidate is a pyrrole etomidate analog that is 3 orders of magnitude less potent an inhibitor of in vitro cortisol synthesis than etomidate (an imidazole) and does not inhibit in vivo steroid production. Although carboetomidate's reduced functional effect on steroid synthesis is thought to reflect lower binding affinity to 11β-hydroxylase, differential binding to this enzyme has never been experimentally demonstrated. In the current study, we tested the hypothesis that carboetomidate and etomidate bind with differential affinity to 11β-hydroxylase by comparing their abilities to inhibit photoaffinity labeling of purified enzyme by a photoactivatable etomidate analog and to modify the enzyme's absorption spectrum in a way that is indicative of ligand binding. In addition, we made a preliminary exploration of the manner in which etomidate and carboetomidate might differentially interact with this site using spectroscopic methods as well as molecular modeling techniques to better understand the structural basis for their selectivity.MethodsThe ability of azi-etomidate to inhibit cortisol synthesis was tested by assessing its ability to inhibit cortisol synthesis by H295R cells. The binding affinities of etomidate and carboetomidate to 11β-hydroxylase were compared by assessing their abilities to (1) inhibit photoincorporation of the photolabile etomidate analog [(3)H]azi-etomidate into the enzyme and (2) modify the absorption spectrum of the enzyme's heme group. In silico docking studies of etomidate, carboetomidate, and azi-etomidate binding to 11β-hydroxylase were performed using the computer software GOLD.ResultsSimilar to etomidate, azi-etomidate potently inhibits in vitro cortisol synthesis. Etomidate inhibited [(3)H]azi-etomidate photolabeling of 11β-hydroxylase in a concentration-dependent manner. At a concentration of 40 µM, etomidate reduced photoincorporation of [(3)H]azi-etomidate by 96% ± 1% whereas carboetomidate had no experimentally detectable effect. On addition of etomidate to 11β-hydroxylase, a type 2 difference spectrum was produced indicative of etomidate complexation with the enzyme's heme iron; carboetomidate had no effect whereas azi-etomidate produced a reverse type 1 spectrum. Computer modeling studies predicted that etomidate, carboetomidate, and azi-etomidate can fit into the heme-containing pocket that forms 11β-hydroxylase's active site and pose with their carbonyl oxygens interacting with the heme iron and their phenyl rings stacking with phenylalanine-80. However, additional unique poses were identified for etomidate and azi-etomidate that likely account for their higher affinities.ConclusionsCarboetomidate's reduced ability to suppress in vitro and in vivo steroid synthesis as compared with etomidate reflects its lower binding affinity to 11β-hydroxylase and may be attributed to carboetomidate's inability to form a coordination bond with the heme iron located at the enzyme's active site.

Dataset Information

The etomidate analog ET-26 HCl retains superior myocardial performance: Comparisons with etomidate in vivo and in vitro.

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The etomidate analog ET-26 HCl retains superior myocardial performance: Comparisons with etomidate in vivo and in vitro.

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